Synthesis and preliminary evaluation of phenyl 4-123I-iodophenylcarbamate for visualization of cholinesterases associated with Alzheimer disease pathology

Abstract

Acetylcholinesterase and butyrylcholinesterase accumulate with brain ?-amyloid (A?) plaques in Alzheimer disease (AD). The overall activity of acetylcholinesterase is found to decline in AD, whereas butyrylcholinesterase has been found to either increase or remain the same. Although some cognitively normal older adults also have A? plaques within the brain, cholinesterase-associated plaques are generally less abundant in such individuals. Thus, brain imaging of cholinesterase activity associated with A? plaques has the potential to distinguish AD from cognitively normal older adults, with or without A? accumulation, during life. Current A? imaging agents are not able to provide this distinction. To address this unmet need, synthesis and evaluation of a cholinesterase-binDing ligand, phenyl 4-123I-iodophenylcarbamate (123I-PIP), is described. Methods: Phenyl 4-iodophenylcarbamate was synthesized and evaluated for binDing potency toward acetylcholinesterase and butyrylcholinesterase using enzyme kinetic analysis. This compound was subsequently rapidly radiolabeled with 123I and purified by high-performance liquid chromatography. Autoradiographic analyses were performed with 123I-PIP using postmortem orbitofrontal cortex from cognitively normal and AD human brains. Comparisons were made with an A? imaging agent, 2-(4?-dimethylaminophenyl)-6-123I-iodo-imidazo[1,2-a]pyridine (123I-IMPY), in adjacent brain sections. Tissues were also stained for A? and cholinesterase activity to visualize A? plaque load for comparison with radioligand uptake. Results: Synthesized and purified PIP exhibited binDing to cholinesterases. 123I was successfully incorporated into this ligand. 123I-PIP autoradiography with human tissue revealed accumulation of radioactivity only in AD brain tissues in which A? plaques had cholinesterase activity. 123I-IMPY accumulated in brain tissues with A? plaques from both AD and cognitively normal individuals. Conclusion: Radiolabeled ligands specific for cholinesterases have potential for use in neuroimaging AD plaques during life. The compound herein described, 123I-PIP, can detect cholinesterases associated with A? plaques and can distinguish AD brain tissues from those of cognitively normal older adults with A? plaques. Imaging cholinesterase activity associated with A? plaques in the living brain may contribute to the definitive diagnosis of AD during life.